It is the long range plan of this project to evaluate actions of receptors for toxic halogenated aromatics and estrogenically- active chemicals in relation to hepatotoxic potency of these compounds. These studies focus on receptor mediated effects on gene expression critical to tumor promotion using the rat two- stage model for hepatocarcinogenesis. The compounds of special interest are 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), structurally-related polychlorinated dibenzodioxins and dibenzofurans, diethystilbestrol, 17 alpha-ethinylestradiol and alpha-zearalanol. The objectives of these studies are to evaluate the quantitative relationships between dose of tumor promoter, receptor interactions, DNA adducts (by 32P-postlabelling), critical changes in gene expression, including oncogene activation, and histopathological alterations including preneoplastic lesions and tumor incidence. Furthermore, the time course of these changes is being investigated. The rat two-stage model is employed as the primary model for hepatocarcinogenesis. This model uses a single dose of an initiating agent followed by chronic exposure to a promoting agent. A number of potentially important observations have been made in livers from animals at various stages of the carcinogenic process. These findings involve alterations in receptor and signal transduction pathways important to regulation of cell proliferation. Future studies are designed to localize these changes in neoplastic cells. Furthermore, attempts will be made to develop in vitro models for the purpose of obtaining data on structure-activity relationships.